Synthesis of 3-aminopyridin-2(1H)-ones and 1H-pyrido[2,3-b][1,4]oxazin- 2(3H)-ones

Article abstract of DOI:10.1007/s10593-014-1464-9

The interaction of 1,3-diketones with chloroacetamide produced N-(3-oxoalkenyl)chloroacetamides. Heating of N-(3-oxoalkenyl)chloroacetamides with an excess of pyridine in ethanol or butanol led to the formation of pyridin-2(1H)-ones, substituted with a py

Full text of DOI:10.1007/s10593-014-1464-9

Chemistry of Heterocyclic Compounds, Vol. 50, No. 2, May, 2014 (Russian Original Vol. 50, No. 2, February, 2014)
SYNTHESIS OF 3-AMINOPYRIDIN-2(1Н)-ONES
AND 1H-PYRIDO[2,3-b][1,4]OXAZIN-2(3H)-ONES
1
1
A. S. Fisyuk1,2 , I. V. Kulakov , D. S. Goncharov ,
*
O. S. Nikitina1, Y. P. Bogza1, and A. L. Shatsauskas1
The interaction of 1,3-diketones with chloroacetamide produced N-(3-oxoalkenyl)chloroacetamides.
Heating of N-(3-oxoalkenyl)chloroacetamides with an excess of pyridine in ethanol or butanol led to the
formation of pyridin-2(1Н)-ones, substituted with a pyridine ring at position 3. The reactions of these
compounds with hydrazine hydrate produced 3-aminopyridin-2(1Н)-ones. The synthesis of
1H-pyrido[2,3-b][1,4]oxazin-2(3H)-ones was accomplished by a reaction of 3-aminopyridin-2(1Н)-
ones with chloroacetyl chloride.
Keywords: 3-aminopyridin-2(1Н)-ones, enamino ketones, N-(3-oxoalkenyl)amides, chloroacetamides,
intramolecular cyclization.
3-Aminopyridin-2(1Н)-ones are of interest as biologically active compounds [1, 2], some of which are
in clinical use, such as amrinone [3]. The presence of an incorporated amino acid fragment makes
3-aminopyridin-2(1Н)-ones attractive as building blocks for the synthesis of peptidomimetics [4, 5], including
agonists for the GPR142 receptor, which is one of the receptors conjugated with the G-protein, and which may
lead to a range of disorders in cases of abnormal function [6].
The methods for the preparation of 3-aminopyridin-2(1Н)-ones are typically based on transformations
of 3-nitro- [7] and 3-cyanopyridin-2(1Н)-ones [1]. We have previously developed methods for the synthesis of
pyridin-2-ones and 5,6-dihydropyridin-2(1Н)-ones from pyridinium and phosphonium salts, obtained from
_______
*To whom correspondence should be addressed, e-mail: fisyuk@chemomsu.ru.
1Omsk F. M. Dostoevsky State University, 55a Mira Ave., Omsk 644077, Russia.
2Omsk State Technical University, 11 Mira Ave., Omsk 644050, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 241-249, February, 2014. Original
article submitted December 28, 2013.
0009-3122/14/5002-0217©2014 Springer Science+Business Media New York
217

N-(3-oxoalkyl)chloroacetamides [8, 9]; the possibility of intramolecular cyclization of enamino ketone amides
to pyridin-2(1Н)-ones has been demonstrated [10, 11]. An analogous approach to the synthesis of 3-amino-
4,6-dimethylpyridin-2(1Н)-one was demonstrated by Gewald et al. [12]. The starting material for the synthesis
of 3-amino-4,6-dimethylpyridin-2(1Н)-one was the enamino ketone 1a, from which the chloroacetamide 2a was
obtained [12]. Heating compound 2а with pyridine in butanol led to the formation of the salt 3a, which was
cyclized under the reaction conditions to the 3-pyridylpyridin-2(1Н)-one 4a. The 3-amino-4,6-dimethylpyridin-
2(1Н)-one (5a) was obtained by a subsequent cleavage of the pyridine ring in compound 4а with hydrazine
hydrate.
Since this method was previously used for the preparation of only the 3-aminopyridin-2(1Н)-one 5а, we
were interested in its applicability to the synthesis of other 3-aminopyridin-2(1Н)-ones, compounds 5b,с. In order
to further simplify the method, we investigated the possibility of obtaining the starting compounds 2а-с while
bypassing the preparation of enamino ketones 1а-с, through heating the 1,3-diketones 6а-с with
chloroacetamide in benzene in a flask equipped with a Dean–Stark trap (method A). For the purpose of
comparing the methods, compounds 2a-c were also obtained by acylation of the enamino ketones 1а-с, prepared
from 1,3-diketones 6а-с and ammonium acetate [13] (method B). The decreased number of synthetic steps
allowed us to achieve a significantly higher yield of the products 2a,b. The yields of the products 2а-с obtained
according to both methods are presented in the Table 1.
The most characteristic absorption bands in the IR spectra of the β-enamino ketone chloroacetamides
2a-с were those of the ketone carbonyl group at 1713-1694 cm-1, as well as the two amide carbonyl bands at
1640-1627 and 1601-1589 cm-1 (Table 2). It should be pointed out that the IR spectra of compounds 2a-с
recorded in СHCl3 exhibited also weak absorption bands at 3250-3150 cm-1 due to the hydrogen bonded NH
group. The NH protons gave 1H NMR signals at 12.9-13.4 ppm, which also confirmed cis configuration with an
intramolecular hydrogen bond for compounds 2а-с.
R1
R1
R1
R2
R3
R2
R3
R2
R3
AcONH4
PhH,
ClCH2COCl
Py, CHCl3
O
O
O
NH2
1a–c
NHCOCH2Cl
2a–c
O
6a–c
Py
ClCH2CONH2
p-TSA, PhH,
EtOH (n-BuOH)
h
R1
R1
R1
R2
R3
NH2
O
R2
R3
Py+Cl–
R2
R3
N2H4, H2O
h
O
Cl–
NHCOCH2Py+
N
H
5a–c
N
H
4a–c
O
3a–c
a R1 = Me, R2 = H, R3 = Me; b R1 = Ph, R2 = H, R3 = Me; c R1 = Me, R2 + R3 = (CH2)4
Heating compounds 2a-с for 7-12 h with excess pyridine in ethanol led to the pyridine salts 4a-c in 84-
93% yields (Table 1). The reaction time could be decreased to 3 h by using a solvent with higher boiling point,
1
such as n-butanol. The structure of the compounds was confirmed by elemental analysis (Table 1), IR, H and
13С NMR spectroscopy (Table 2).
A ketone carbonyl vibration band in the IR spectra of the pyridinium salts 4а-c is absent. The 1H NMR
spectra contained no signal for the methylene fragment at the α-position relative to the carbamoyl group, while
new signals appeared at 8.1-9.2 ppm that were characteristic of the pyridinium ring protons.
218

TABLE 1. Physicochemical Characteristics of Compounds 2a-c, 4a-c,
5a-c, 7a,b, 8a,b, 9a,b
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %
(method)
Mp,°C
С
H
N
C7H10ClNO2
C12H12ClNO2
C10H14ClNO2
––
––
––
67-68 (67-68 [10])
75 (A)
68 (B)
53*
64 (A)
68 (B)
29*
27 (A)
87 (B)
45*
2a
2b
2c
60.95
60.64
5.02
5.09
6.20
5.89
64-65
oil
55.37
55.69
6.33
6.54
6.17
6.49
C12H13ClN2O
C17H15ClN2O
––
––
––
>290 (303-305 [12])
>290
84
90
4a
4b
68.10
4.82
11.66
68.34
5.06
11.87
C15H17ClN2O
65.40
65.10
6.10
6.19
10.31
10.12
>290
93
4c
C7H10N2O
C12H12N2O
––
––
––
202-203 (200-202 [12])
194-195
66
69
5a
5b
72.10
6.13
13.91
71.98
6.04
13.99
C10H14N2O
67.26
67.39
7.78
7.92
15.79
15.72
>260 (decomp.)
219-220
57
47
69
5c
7a
7b
8a
C9H11ClN2O2
C14H13ClN2O2
C9H10N2O2
49.93
5.42
13.29
50.36
5.17
13.05
60.21
60.77
5.09
4.74
10.51
10.12
204-205
60.92
5.89
16.11
200-202
51 (A)
81 (B)
60.66
5.66
15.72
C14H12N2O2
C16H18N4O4
C26H22N4O4
70.23
69.99
5.34
5.03
11.87
11.66
180-181
210-211
180-183
55
26
19
8b
9a
9b
58.56
5.85
17.38
58.17
5.49
16.96
68.40
68.71
5.27
4.88
12.76
12.33
_______
*Yield according to the method B, calculated from the diketone 6а-c.
The 3-aminopyridin-2(1H)-ones 5a-c were obtained in 57-69% yields by heating compounds 4a-c in a
50% hydrazine hydrate solution. An increase of the hydrazine hydrate concentration to 80% slightly improved
the yield.
The IR spectra of compounds 5a-c contained N–H stretching vibration bands at 3361-3283 and 3452-
1
3400 cm-1. The amino group protons were observed in the H NMR spectra at the region of 4.2-4.4 ppm as
broadened singlets.
The 3-aminopyridin-2(1Н)-ones are binucleophiles that could be used in the synthesis of pyridine
derivatives condensed at the С(2)–С(3) bond, such as 1H-pyrido[2,3-b][1,4]oxazines, for which there are only a
few preparative methods described [14-17].
We also studied the reaction of compounds 5a,b with chloroacetyl chloride. Compounds 5a,b were quite
smoothly acylated at room temperature in dichloromethane medium in the presence of pyridine, but the products
7a,b were formed in only moderate yields (45-55%). Changing the medium from dichloromethane to DMF and
increasing the temperature to 80-100°С led to the cyclization of the intermediate chloroacetamides 7a,b to the
1H-pyrido[2,3-b][1,4]oxazin-2(3H)-ones 8a,b. It should be noted that the attempts at substituting the chlorine
atom by nitrogen upon heating compound 7а with aniline also resulted in the product 8а. The same compound
was formed when heating the chloroacetamide 7а with K2CO3 in DMF. A comparison of the 1H NMR spectra of
compounds 7a,b and 8a,b indicated that the pyridine ring proton gave a signal shifted downfield by 0.5-1.0 ppm
after the cyclization reaction.
219

220

221

We did not succeed in obtaining the 1H-pyrido[2,3-b][1,4]oxazine-2,3-diones 8a,b from the 3-amino-
pyridin-2-ones 5a,b and diethyl oxalate. Heating compounds 5a,b with a 1.5-fold excess of diethyl oxalate for
3-4 h at 150°С gave the diamides 9a,b. A brief heating of the reagents gave a mixture of the products 9а,b and
10a,b, the formation of which was observed by 1H NMR spectroscopy.
The 1H NMR spectra of compounds 9a,b contained two broadened signals at 9.35-9.42 and 11.49-11.83
ppm of protons bound to nitrogen atoms, while there was no significant change in the chemical shift of the
proton at the С-5 atom in compound 10а and in the obtained products 9а,b.
Thus, we have significantly simplified the method for the preparation of N-(3-oxoalkenyl)chloro-
acetamides and 3-pyridylpyridin-2(1Н)-ones. The modified method allows the preparation of 3-aminopyridin-
2(1H)-ones from 1,3-diketones in three stages. It was shown that 3-aminopyridin-2(1H)-ones can be used for
the synthesis of 1H-pyrido[2,3-b][1,4]oxazin-2(3H)-ones.
EXPERIMENTAL
IR spectra were recorded on an FT-801 FTIR spectrometer in СHCl3 (compounds 2a-c) and in KBr
pellets (the rest of the compounds). 1H and 13C NMR spectra were acquired on a Bruker DRX-400 spectrometer
(400 and 100 MHz, respectively). The internal standard was TMS. Elemental analysis was performed on a Carlo
Erba 1106 CHN elemental analyzer. Melting points were determined on a Kofler bench. The reaction progress
and the purity of the obtained compounds was controlled by TLC on Sorbfil AF-A-UV plates. The enamino
ketones 1a-с were obtained by heating benzene solutions of the 1,3-dicarbonyl compounds 6а-с with
ammonium acetate, while using a flask with a Dean–Stark trap [13]. The yield of compound 1a was 78%,
compound 1b – 43%, compound 1c – 52%. The IR and NMR spectra of compounds 2а, 4а, 5а fully matched
those of the previously described compounds [10, 12].
N-(1-Methyl-3-oxobut-1-en-1-yl)-2-chloroacetamide (2a), N-(3-Oxo-1-phenylbut-1-en-1-yl)-2-chloro-
acetamide (2b), N-(2-Acetylcyclohex-1-en-1-yl)-2-chloroacetamide (2c) (General Method). А. The diketone
6a-c (20 mmol) was dissolved in benzene (20 ml), followed by the addition of chloroacetamide (2.413 g,
222

26 mmol) and p-toluenesulfonic acid (0.950 g, 5 mmol). The reaction mixture was refluxed for 24 h in a flask
with a reflux condenser and a Dean–Stark trap. After the reaction was complete, the mixture was passed through
a Schott filter in order to remove the excess chloroacetamide, and the residue was washed with benzene. The
organic fractions were combined, washed with water to neutral pH, and dried over Na2SO4. Benzene was
removed at reduced pressure. The product was purified by recrystallization from hexane.
B. Chloroacetyl chloride (0.84 ml, 1.186 g, 10.5 mmol) was added dropwise with stirring to a mixture
of the enamino ketone 1a-с (10.0 mmol) and anhydrous pyridine (1.0 ml, 11.0 mmol) in anhydrous chloroform
(15 ml). The mixture was cooled with ice and stirred for 1 h, then at room temperature for 1-5 h. Then the
mixture was diluted with chloroform (10 ml), washed with 10% HCl solution (30 ml) and with water to neutral
pH. The organic phase was dried over anhydrous Na2SO4, and chloroform was removed by evaporation. The
residue was purified by recrystallization from a 4:7 mixture of ethyl acetate and hexane (compound 2a) or by
flash chromatography on alumina (gradient elution with 3:7 → 6:4 dichloromethane–hexane).
Synthesis of the (2-Oxo-1,2-dihydropyridin-3-yl)pyridinium Chlorides 4a-с (General Method).
Pyridine (2.4 ml, 30 mmol) was added to a solution of chloroacetamide 2a-с (10 mmol) in absolute ethanol
(20 ml). The reaction mixture was heated in a flask with a reflux condenser for 7-12 h. Substituting ethanol with
n-butanol shortened the reaction time to 3-5 h. The solvent was removed by evaporation, the residue was
triturated with anhydrous acetone, the solids were filtered off, washed on the filter with several portions of
acetone, and dried at elevated temperature under reduced pressure.
Synthesis of 3-Aminopyridin-2(1H)-ones 5a-с (General Method). The pyridinium salt 4а-c
(10 mmol) was dissolved in 50% hydrazine hydrate (4.9 ml, 50 mmol). The mixture was heated in a flask with a
reflux condenser for 3 h, cooled, and diluted with water (5.0 ml). The precipitate was filtered off and
recrystallized from a 1:1 mixture of ethanol and water.
N-(4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-2-chloroacetamide (7a). Pyridine (1.0 ml, 12 mmol)
was added to a solution of 3-amino-4,6-dimethylpyridin-2(1Н)-one (5а) (828 mg, 6 mmol) in dichloromethane
(20 ml), the mixture was cooled to 5°С, and chloroacetyl chloride (1.0 ml, 12 mmol) was added dropwise. The
mixture was stirred at room temperature for 15 h. The solvent was removed by evaporation, and the residue was
treated with ice-cold water. The precipitate formed was filtered off, washed with distilled water, and
recrystallized from 50% ethanol. Yield 600 mg. White needle shaped crystals.
N-(6-Methyl-2-oxo-4-phenyl-1,2-dihydropyridin-3-yl)-2-chloroacetamide (7b) was obtained
analogously from 3-amino-4-phenylpyridin-2-one 5b (0.2 g, 1 mmol) and chloroacetyl chloride (0.17 ml,
2 mmol), using recrystallization from 70% ethanol.
6,8-Dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (8a). А. A solution of 3-amino-4,6-dimethyl-
pyridin-2(1Н)-one (5а) (207 mg, 1.5 mmol) in DMF (5 ml) was treated with K2CO3 (414 mg, 3.0 mmol), then
chloroacetyl chloride (0.2 ml, 3.0 mmol) was added dropwise with cooling. The mixture was stirred for 15 h at
80-100°С. Then the reaction mixture was cooled and poured into a beaker with ice-cold water (150 ml). The
aqueous layer was extracted with chloroform (3×25 ml), the organic layer was dried over CaCl2, the solvent was
removed by distillation, and the residue was triturated with hexane. The crude product was recrystallized from a
1:1 mixture of 2-PrOH and hexane. Yield 136 mg.
B. A solution of N-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-2-chloroacetamide (7a) (215 mg,
1.0 mmol) in DMF (3 ml) was treated with K2CO3 (207 mg, 1.5 mmol) and aniline (93 mg, 1.0 mmol). The
mixture was stirred for 5 h at 80°С, then cooled, and poured into a beaker with ice-cold water (100 ml). The
aqueous layer was extracted with chloroform (3×25 ml), the organic layer was dried over CaCl2, the solvent was
removed by evaporation, the residue was triturated with hexane. The crude product was recrystallized from a
1:1 mixture of 2-PrOH and hexane, giving 144 mg of the product 8а. Analogous results were obtained also by
heating compound 7а in DMF with K2CO3 and without aniline.
6-Methyl-8-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (8b). Obtained analogously to compound
8а (method А) from 3-amino-6-methyl-4-phenylpyridine-2(1Н)-one (5b) (200 mg, 1 mmol) and chloroacetyl
chloride (226 mg, 2 mmol). After the reaction was complete, the solution was cooled and poured into a beaker
223

with ice water slurry. The precipitated white needle shaped crystals were filtered off, washed with water, and
dried. Yield 131 mg.
N,N'-Bis(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)ethanediamide (9a). Diethyl oxalate (0.4 ml,
3 mmol) was added to 3-amino-4,6-dimethylpyridine-2(1Н)-one (5а) (276 mg, 2 mmol), and the mixture was
refluxed for 3 h. Then 2-PrOH (1 ml) was added and the mixture was refluxed for an additional 1 h. The
precipitate formed upon cooling was filtered off, washed with cold 2-PrOH, and dried. Yield 102 mg. White
fine crystalline powder. An analytically pure sample was obtained by recrystallization from a 1:3 mixture of
DMF and 2-PrOH.
N,N'-Bis(6-methyl-2-oxo-4-phenyl-1,2-dihydropyridin-3-yl)ethanediamide (9b). Obtained analogously
to compound 9a from 3-amino-4-phenylpyridin-2-one 2b (200 mg, 1.0 mmol) and diethyl oxalate (0.2 ml,
1.5 mmol). Yield 49 mg. White fine crystalline powder. An analytically pure sample was obtained by
recrystallization from a 1:3 mixture of DMF and 2-PrOH.
This work received financial support from the Russian Foundation for Basic Research (project 11-03-
00338-а) and the Ministry of Education and Science of the Russian Federation in the framework of the project
2596.
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